Deficiency of the scavenger receptor class B type I (SR-BI) protein in mice is associated with significantly increased plasma HDL-C levels, paradoxically accelerated atherosclerosis despite increased HDL-C levels, and infertility in female mice. We were the first to report associations with these same phenotypes in humans with certain SR-BI gene (SCARB1) single nucleotide polymorphisms (SNPs). Among these SNPs, rs10846744, a noncoding SNP (G>C) within intron 1 located at a regulatory site, was significantly associated with increased subclinical atherosclerosis (SCA) and increased odds for cardiovascular disease (CVD) in Multi-Ethnic Study of Atherosclerosis (MESA) participants. Importantly, inclusion of traditional CVD risk factors in a multivariate regression model did not attenuate the association of rs10846744 with CVD, strongly suggesting that other pathway(s), including an inflammatory one, likely drive this important clinical association. We used RNA-Seq to examine transcriptional differences in gene expression between lymphocytes isolated from hyperalphalipoproteinemic (HALP) carriers homozygous for the SCARB1 rs10846744 reference (GG) allele with carriers homozygous for the risk (CC) allele. We identified lymphocyte activation gene-3 (LAG-3, on chromosome 12p13.31), a gene that encodes LAG-3 protein, and which binds major histocompatibility complex II to suppress expansion of T effector cells, as a strong candidate in the rs10846744 CVD risk pathway. The hypothesis to be tested in this application is that LAG-3 protein deficiency, via a pro-inflammatory effect, exerts a major influence in the association of the SCARB1 rs10846744 SNP with SCA and CVD. We will use three specific aims to test the hypothesis: (1) To determine the mechanism of LAG-3 protein in regulating the pro-inflammatory state of SCARB1 rs10846744 risk (CC) cells, (2) To determine the effect of LAG-3 protein deficiency in a murine model of atherosclerosis, and (3) To examine LAG-3 protein as an independent predictor of SCA and CVD risk in MESA. The long term objective of this project is to unravel the novel intersection of the SCARB1 rs10846744 variant and the immune checkpoint inhibitor LAG-3 protein in CVD risk.